HIV protease is an important chemotherapeutic target for the treatment of AIDS; the most successful treatments developed to date involve combinations of protease inhibitors with nucleoside analogs which inhibit the reverse transcriptase. However, the high mutation rate of the virus makes it possible to select against most of the protease inhibitors which thus far have been developed. Nearly all of the reported crystallographic and NMR spectroscopic characterizations of HIV protease involve enzyme-inhibitor complexes. In the case of NMR, this is almost a requirement, since the uncomplexed enzyme is rapidly degraded due to autolysis. In collaboration with Paul Wingfield, we have recently initiated studies of an autolysis resistant mutant developed by Mildner et al. (Biochemistry 33, 9405-9413; 1994). It is anticipated that by working with an autolysis resistant mutant, interactions with weaker inhibitors can be studied which will lead to enhanced understanding of binding interactions and protease dynamics. These NMR studies are currently in progress. In addition, the group has recently synthesized several potential protease inhibitors. The best of these has an apparent inhibition constant of ~ 500 nM, and additional inihibitors of this type are currently under evaluation. Finally, we have recently performed a series of theoretical calculations on this enzyme in order to better understand the interactions which stabilize the dimeric structure.